U.S. patent application number 12/856089 was filed with the patent office on 2011-06-09 for tetrahydro-isoalpha acid compositions and methods for weight management.
This patent application is currently assigned to Metaproteomics, LLC. Invention is credited to Gary Darland, Veera Konda, Matthew L. Tripp.
Application Number | 20110136917 12/856089 |
Document ID | / |
Family ID | 43586518 |
Filed Date | 2011-06-09 |
United States Patent
Application |
20110136917 |
Kind Code |
A1 |
Tripp; Matthew L. ; et
al. |
June 9, 2011 |
TETRAHYDRO-ISOALPHA ACID COMPOSITIONS AND METHODS FOR WEIGHT
MANAGEMENT
Abstract
Compositions and methods to promote or maintain weight loss
utilizing tetrahydro-isoalpha acid compounds are disclosed. Methods
to increase synthesis of GLP-1 are disclosed.
Inventors: |
Tripp; Matthew L.; (Gig
Harbor, WA) ; Darland; Gary; (Port Orchard, WA)
; Konda; Veera; (Gig Harbor, WA) |
Assignee: |
Metaproteomics, LLC
San Clemente
CA
|
Family ID: |
43586518 |
Appl. No.: |
12/856089 |
Filed: |
August 13, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61234091 |
Aug 14, 2009 |
|
|
|
Current U.S.
Class: |
514/690 |
Current CPC
Class: |
A61P 3/04 20180101; G01N
2800/34 20130101; A61P 9/00 20180101; G01N 2800/321 20130101; A61P
3/00 20180101; G01N 2800/02 20130101; A61P 9/12 20180101; A61P 3/10
20180101; A61P 3/06 20180101; G01N 2800/042 20130101; A61P 19/10
20180101; G01N 33/6893 20130101; G01N 2800/36 20130101 |
Class at
Publication: |
514/690 |
International
Class: |
A61K 31/12 20060101
A61K031/12; A61P 3/00 20060101 A61P003/00; A61P 9/00 20060101
A61P009/00; A61P 19/10 20060101 A61P019/10 |
Claims
1. A method to promote healthy weight management in a mammal in
need thereof, said method comprising administering a composition
comprising a therapeutically effective amount of a
tetrahydro-isoalpha acid.
2. The method according to claim 1, wherein the composition
comprises from 50 mg to 10,000 mg of the tetrahydro-isoalpha
acid.
3. The method according to claim 2, wherein said
tetrahydro-isoalpha acid is selected from the group consisting of
tetrahydro-isohumulone, tetrahydro-isocohumulone, and
tetrahydro-isoadhumulone.
4. The method according to claim 1, wherein promoting healthy
weight management is selected from promoting weight loss or
retarding weight gain in a mammal in need thereof.
5. The method according to claim 1, wherein the subject in need has
a condition selected from the group consisting of diabetes,
cardiovascular disease, dyslipidemia, hypertension, erectile
dysfunction, polycystic ovary syndrome, end stage renal disease,
osteoporosis, nonalcoholic steatohepatitis, obesity, and sleep
apnea.
6. The method according to claim 1, wherein said administration
reduces food cravings or increases satiety.
7. The method according to claim 1, wherein said administration
increases GLP-1 synthesis.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This patent application claims priority to U.S. Provisional
Application Ser. No. 61/234,091 filed on Aug. 14, 2009.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates generally to compositions and
methods comprising tetrahydro-isoalpha acid compounds that can be
used to promote weight loss or retard weight gain in a mammal in
need.
[0004] 2. Description of the Related Art
[0005] Obesity and overweight may be defined as excessive or
abnormal fat accumulation which may impair health. The distinction
between obesity and overweight are (1) simply matters of degree.
The World Health Organization (WHO) defines "overweight" as a BMI
(body mass index) equal to or greater than 25 and "obesity" as a
BMI equal to or greater than 30. WHO further notes that there is
evidence that the risk of chronic diseases in populations increases
progressively from a BMI of 21.
[0006] WHO's 2005 projections estimated that approximately 1.6
billion adults (age 15+) were overweight; and at least 400 million
adults were obese. The Organization further projects that by 2015,
approximately 2.3 billion adults will be overweight and more than
700 million will be obese.
[0007] Obesity and overweight results from an energy imbalance
between calories consumed and calories expended and may be
attributed, in part, to a trend towards decreased physical activity
(due largely to the increasingly sedentary nature of many forms of
work as well as technology in the home, and more passive leisure
pursuits), changing modes of transportation, and increasing
urbanization coupled with a shift in diet towards increased intake
of energy-dense foods that are high in fat and sugars but low in
vitamins, minerals and other micronutrients.
[0008] The health consequences of such fat accumulation include
increased risk of cardiovascular disease, some cancers (breast,
colon, and endometrial), musculoskeletal disorders (e.g.,
osteoarthritis) and diabetes.
(www.who.int/mediacentre/factsheets/fs311/en/index.html; last
viewed Aug. 2, 2010).
[0009] Recognition of these health consequences has steadily
increased and weight management has progressed from the realm of
physical aesthetics to a medical problem requiring intervention
(e.g., pharmaceutical or surgical) to lifestyle management
including changes in diet and exercise for the afflicted
individual. One recurring problem most often associated with
lifestyle management is the failure to either lose the weight
initially or to maintain the weight loss over time, especially as
the individual transitions to a self policed lifestyle management
program.
[0010] Numerous phytochemical or herbal based weight reduction
products or systems have been investigated over the years
including, for example, those centered around jojoba (U.S. Pat. No.
7,138,134), Cissus, Vernonia, and Brillantasia (U.S. Pat. Nos.
7,175,589 and 7,736,675), the phytochemical Diindolylmethane (DIM),
as well as its precursor, Indole-3-carbinol (I3C), and cogener,
2-(Indol-3-ylmethyl)-3,3' diindolylmethane (LTR-1) (U.S. Pat. No.
6,534,085), or Ferula hermonis (U.S. Pat. No. 6,780,440). All have
achieved a limited degree of commercial success attributable, in
part, to difficulties in maintaining product use or system
compliance over time. Additionally, weight control problems may
occur over time in the transition from the "diet" regimen to the
day-to-day "normal" lifestyle once weight has been lost.
[0011] Another area for obesity control research has centered on
GLP-1 (glucagon-like peptide-1). Enteroendocrine cells have
important roles in regulating energy intake and glucose homeostasis
through their actions on peripheral target organs, including the
endocrine pancreas. Proglucagon synthesized by L cells found in the
distal ileum and colon, is posttranslationally processed into GLP-1
(glucagon-like peptide-1), a potent insulin secretagogue (Drucker D
J 1998 Glucagon-like peptides. Diabetes 47:159-169). Glucagon-like
peptide 1 (GLP-1)1 is known as an insulinotropic hormone exerts its
effects on glucose homeostasis in regulating 1) islet hormone
function (insulin and glucagon), 2) nutrient delivery, and 3) food
intake. Intra-cerebroventricular administration of GLP-1 was found
to inhibit eating and reduce body weight in rats (Turton M. D,
1996; Meeran K, 1999).
[0012] In human clinical trials, liraglutide, a stable GLP-1 mimic
(2 amino acid changes in GLP-1, 97% homology) dose dependently
reduced the body weight with cardiovascular beneficial effects such
as reduced blood pressure and triglyceride content in patients with
T2DM (reviewed in Pratley 2008, Sulistio, 2009).
[0013] GLP-1 levels increase in blood within minutes of food
intake, well before any food appears in the gut, suggesting a
neural signal to the L cells (Drucker 2006). GLP-1, a 30 amino acid
peptide derived from proglucagon gene. GLP-1 was shown to regulate
by multiple mechanism including proglucagon gene regulation, DPP-4
inhibition and G protein-coupled receptor (GPR) signaling pathways.
Many factors including glucose load, oils (corn and perilla), and
non-digestable carbohydrates involved in GLP-1 secretion (Irini
1999, Cani, 2007, Lu 2008).
[0014] Recently, it was reported that unsaturated long-chain fatty
acids (such as a-linolenic acid) promote the secretion of GLP-1 via
GPR120, which is expressed predominantly in the colon (Hirasawa A,
2008). M2 receptors antagonist (atropine & Pirenzepine) block
the corn oil induced GLP-1 suggesting the role of M2 receptors in
GLP-1 activation (Anini 2002). It was reported that bitter taste
receptors T1R (Dyer, 2005) and T2R (Wu, 2002, Jeon, 2008) express
in the gut and stimulate the release of hormones. Also, GPR 119
involved in glycemic control by enhancing GLP-1 in intestinal
endocrine cells (Chu 2008) and shown beneficial in treatment of T2D
and obesity (Overton, 2008). These data suggesting that multiple
GPR regulate the GLP-1 secretion in L cells.
[0015] In addition to potentiating glucose-induced insulin
secretion, GLP-1 stimulates proinsulin gene expression and
biosynthesis (Drucker D J, Philippe J, Mojsov S, Chick W L, Habener
J F 1987 Glucagon-like peptide I stimulates insulin gene expression
and increases cyclic AMP levels in a rat islet cell line. Proc Natl
Acad Sci USA 84:3434-3438). Furthermore, GLP-1 has been recently
shown to promote satiety and reduce food intake through
interactions with the hypothalamus (Turton M D, O'Shea D, Gunn I,
et al. 1996, Nature 379:69-72; Flint A, Raben A, Astrup A, Holst J
J, 1998 J Clin Invest 101:515-520).
[0016] The inventors had discovered methods and compositions
comprising tetrahydro-isoalpha acid compounds that can be used to
promote weight loss directly or retard weight gain in subjects in
need.
SUMMARY OF THE INVENTION
[0017] The present invention relates generally to compositions and
methods comprising tetrahydro-isoalpha acid compounds that can be
used to promote weight loss or retard weight gain in a mammal in
need.
[0018] A first embodiment of the invention describes a method to
promote healthy weight management in a mammal in need, where the
method comprises administering a composition comprising a
therapeutically effective amount of a tetrahydro-isoalpha acid.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] The patent or application file contains at least one drawing
executed in color. Copies of this patent or patent application
publication with color drawing(s) will be provided by the Office
upon request and payment of the necessary fee.
[0020] FIG. 1 graphically depicts the changes in body weight in
C57BL6/J mice maintained on a standard chow diet (LFD) or high-fat
diets (HFD) alone or in which rosiglitazone (0.5 mg kg.sup.-1
d.sup.-1), THIAA (100 mg kg.sup.-1 d.sup.-1), or Insinase (100 mg
kg.sup.-1 d.sup.-1) were incorporated.
[0021] FIG. 2 graphically depicts the changes in body weight in
C57BL6/J mice maintained on a high-fat diet (HFD) alone or where
THIAA was added to the HFD, or where mice on HFD+THIAA were
switched to HFD alone. * denote statistically significant changes
in body weight relative to HFD diet alone; .fwdarw. denotes
switching or changing diets.
[0022] FIG. 3 graphically depicts the changes in liver weight in
C57BL6/J mice maintained on a standard chow diet (LFD) or high-fat
diets (HFD) alone or in which rosiglitazone (0.5 mg kg.sup.-1
d.sup.-1), THIAA (100 mg kg.sup.-1 d.sup.-1), or Insinase (100 mg
kg.sup.-1 d.sup.-1) were incorporated or switched to alternative
diets as indicated. * denote statistically significant changes in
body weight relative to HFD diet alone; .fwdarw. denotes switching
or changing diets.
[0023] FIG. 4 graphically depicts the changes in gonadal fat weight
in C57BL6/J mice maintained on a standard chow diet (LFD) or
high-fat diets (HFD) alone or in which rosiglitazone (0.5 mg
kg.sup.-1 d.sup.-1), THIAA (100 mg kg.sup.-1 d.sup.-1), or Insinase
(100 mg kg.sup.-1 d.sup.-1) were incorporated or switched to
alternative diets as indicated. * denote statistically significant
changes in body weight relative to HFD diet alone; .fwdarw. denotes
switching or changing diets.
[0024] FIG. 5 graphically depicts the changes in subcutaneous fat
weight in C57BL6/J mice maintained on a standard chow diet (LFD) or
high-fat diets (HFD) alone or in which rosiglitazone (0.5 mg
kg.sup.-1 d.sup.-1), THIAA (100 mg kg.sup.-1 d.sup.-1), or Insinase
(100 mg kg.sup.-1 d.sup.-1) were incorporated or switched to
alternative diets as indicated. * denote statistically significant
changes in body weight relative to HFD diet alone; .fwdarw. denotes
switching or changing diets.
[0025] FIG. 6 graphically depicts representative mice after twelve
weeks on a standard chow diet (LFD) or high-fat diets (HFD) alone
or in which rosiglitazone ("Rosi"; 0.5 mg kg.sup.-1 d.sup.-1),
THIAA (100 mg kg.sup.-1 d.sup.-1), or Insinase (100 mg kg.sup.-1
d.sup.-1) were incorporated.
[0026] FIG. 7 graphically depicts representative mice maintained on
a standard chow diet (LFD) or high-fat diets (HFD) alone or THIAA
(100 mg kg.sup.-1 d.sup.-1) were incorporated or switched to
alternative diets as indicated.
[0027] FIG. 8 graphically depicts the increase in GLP-1 secretion
in NCI-H716 cells following THIA administration compared to
un-stimulated cells
DETAILED DESCRIPTION OF THE INVENTION
[0028] The present invention relates generally to compositions and
methods comprising tetrahydro-isoalpha acid compounds that can be
used to promote weight loss or retard weight gain in a mammal in
need.
[0029] The patents, published applications, and scientific
literature referred to herein establish the knowledge of those with
skill in the art and are hereby incorporated by reference in their
entirety to the same extent as if each was specifically and
individually indicated to be incorporated by reference. Any
conflict between any reference cited herein and the specific
teachings of this specification shall be resolved in favor of the
latter. Likewise, any conflict between an art-understood definition
of a word or phrase and a definition of the word or phrase as
specifically taught in this specification shall be resolved in
favor of the latter.
[0030] Technical and scientific terms used herein have the meaning
commonly understood by one of skill in the art to which the present
invention pertains, unless otherwise defined. Reference is made
herein to various methodologies and materials known to those of
skill in the art. Standard reference works setting forth the
general principles of recombinant DNA technology include Sambrook
et al., Molecular Cloning: A Laboratory Manual, 2nd Ed., Cold
Spring Harbor Laboratory Press, New York (1989); Kaufman et al.,
Eds., Handbook of Molecular and Cellular Methods in Biology in
Medicine, CRC Press, Boca Raton (1995); McPherson, Ed., Directed
Mutagenesis: A Practical Approach, IRL Press, Oxford (1991).
Standard reference works setting forth the general principles of
pharmacology include Goodman and Gilman's The Pharmacological Basis
of Therapeutics, 11th Ed., McGraw Hill Companies Inc., New York
(2006).
[0031] In the specification and the appended claims, the singular
forms include plural referents unless the context clearly dictates
otherwise. As used in this specification, the singular forms "a,"
"an" and "the" specifically also encompass the plural forms of the
terms to which they refer, unless the content clearly dictates
otherwise. Additionally, as used herein, unless specifically
indicated otherwise, the word "or" is used in the "inclusive" sense
of "and/or" and not the "exclusive" sense of "either/or." The term
"about" is used herein to mean approximately, in the region of,
roughly, or around. When the term "about" is used in conjunction
with a numerical range, it modifies that range by extending the
boundaries above and below the numerical values set forth. In
general, the term "about" is used herein to modify a numerical
value above and below the stated value by a variance of 20%.
[0032] As used herein, the recitation of a numerical range for a
variable is intended to convey that the invention may be practiced
with the variable equal to any of the values within that range.
Thus, for a variable that is inherently discrete, the variable can
be equal to any integer value of the numerical range, including the
end-points of the range. Similarly, for a variable that is
inherently continuous, the variable can be equal to any real value
of the numerical range, including the end-points of the range. As
an example, a variable that is described as having values between 0
and 2, can be 0, 1 or 2 for variables that are inherently discrete,
and can be 0.0, 0.1, 0.01, 0.001, or any other real value for
variables that are inherently continuous.
[0033] Reference is made hereinafter in detail to specific
embodiments of the invention. While the invention will be described
in conjunction with these specific embodiments, it will be
understood that it is not intended to limit the invention to such
specific embodiments. On the contrary, it is intended to cover
alternatives, modifications, and equivalents as may be included
within the spirit and scope of the invention as defined by the
appended claims. In the following description, numerous specific
details are set forth in order to provide a thorough understanding
of the present invention. The present invention may be practiced
without some or all of these specific details. In other instances,
well known process operations have not been described in detail, in
order not to unnecessarily obscure the present invention.
[0034] Any suitable materials and/or methods known to those of
skill can be utilized in carrying out the present invention.
However, preferred materials and methods are described. Materials,
reagents and the like to which reference are made in the following
description and examples are obtainable from commercial sources,
unless otherwise noted.
[0035] A first embodiment of the invention describes a method to
promote healthy weight management in a mammal in need, where the
method comprises administering a composition comprising a
therapeutically effective amount of a tetrahydro-isoalpha acid.
[0036] In some aspects of this embodiment the composition comprises
from 50 mg to 10,000 mg of the tetrahydro-isoalpha acid. In yet
other aspects the tetrahydro-isoalpha acid is selected from the
group consisting of tetrahydro-isohumulone,
tetrahydro-isocohumulone, and tetrahydro-isoadhumulone.
[0037] In other aspects of this embodiment, the method promotes
healthy weight management by promoting weight loss or retarding
weight gain in a mammal in need. In some aspects, the mammal in
need has a condition selected from the group consisting of
diabetes, cardiovascular disease, dyslipidemia, hypertension,
erectile dysfunction, polycystic ovary syndrome, end stage renal
disease, osteoporosis, nonalcoholic steatohepatitis, obesity, and
sleep apnea.
[0038] In some aspects, administration of the composition reduces
food cravings or increases satiety in an individual. Additionally,
GLP-1 (glucagon-like peptide-1) synthesis is increase following
administration of the compositions of the invention.
[0039] As used herein, "promoting health weight management" or
variations thereof refers to usages wherein weight loss is
encouraged ("promoting weight loss") or retarding weight gain.
Contemplated usage to retard weight gain include prophylactic use
wherein the invention is used prior to ingestion of a high fat/high
caloric meal to stave off weight gain from that meal, or use in a
maintenance mode subsequent to weight loss from any diet regimen or
treatment as the individual transitions from the active weight loss
program and resumes a more "normal" (at least for that individual)
diet regimen.
[0040] Contemplated use of the invention includes usage, without
limitation, wherein individual weight loss is a direct goal (e.g.,
obesity); where weight loss reduces body stress (e.g.,
osteoporosis) or a side effect from another treatment modality
(e.g., diabetes). In other instances, the weight loss may be
associated with improvement of risk factors associated with a
disease or condition (e.g., erectile dysfunction).
[0041] As used herein, "tetrahydro-isoalpha acid" or "THIAA" refers
to any of one or more of tetrahydro-isoadhumulone,
tetrahydro-isocohumulone and tetrahydro-isohumulone. Structurally,
THIAA comprises compounds of Genus A
##STR00001##
wherein tetrahydro-isohumulone (R=--CH.sub.2CH(CH.sub.3).sub.2);
tetrahydro-isocohumulone (R=CH(CH.sub.3).sub.2); and
tetrahydro-isoadhumulone (R=--CH(CH.sub.3)(CH.sub.2CH.sub.3)) are
shown.
[0042] The term "pharmaceutically acceptable" is used in the sense
of being compatible with the other ingredients of the compositions
and not deleterious to the recipient thereof.
[0043] As used herein, "Insinase" shall refer to a composition
comprising dihydro-isoalpha acids and an alcoholic extract of
Acacia nilotica.
[0044] As used herein, "compounds" may be identified either by
their chemical structure, chemical name, or common name. When the
chemical structure and chemical or common name conflict, the
chemical structure is determinative of the identity of the
compound. The compounds described herein may contain one or more
chiral centers and/or double bonds and therefore, may exist as
stereoisomers, such as double-bond isomers (i.e., geometric
isomers), enantiomers or diastereomers. Accordingly, the chemical
structures depicted herein encompass all possible enantiomers and
stereoisomers of the illustrated or identified compounds including
the stereoisomerically pure form (e.g., geometrically pure,
enantiomerically pure or diastereomerically pure) and enantiomeric
and stereoisomeric mixtures. Enantiomeric and stereoisomeric
mixtures can be resolved into their component enantiomers or
stereoisomers using separation techniques or chiral synthesis
techniques well known to the skilled artisan. The compounds may
also exist in several tautomeric forms including the enol form, the
keto form and mixtures thereof. Accordingly, the chemical
structures depicted herein encompass all possible tautomeric forms
of the illustrated or identified compounds. The compounds described
also encompass isotopically labeled compounds where one or more
atoms have an atomic mass different from the atomic mass
conventionally found in nature. Examples of isotopes that may
incorporated into the compounds of the invention include, but are
not limited to, .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N,
.sup.18O, .sup.17O, etc. Compounds may exist in unsolvated forms as
well as solvated forms, including hydrated forms and as N-oxides.
In general, compounds may be hydrated, solvated or N-oxides.
Certain compounds may exist in multiple crystalline or amorphous
forms. Also contemplated within the scope of the invention are
congeners, analogs, hydrolysis products, metabolites and precursor
or prodrugs of the compound. In general, unless otherwise
indicated, all physical forms are equivalent for the uses
contemplated herein and are intended to be within the scope of the
present invention.
[0045] Compounds according to the invention may be present as
salts. In particular, pharmaceutically acceptable salts of the
compounds are contemplated. A "pharmaceutically acceptable salt" of
the invention is a combination of a compound of the invention and
either an acid or a base that forms a salt (such as, for example,
the magnesium salt, denoted herein as "Mg" or "Mag") with the
compound and is tolerated by a subject under therapeutic
conditions. In general, a pharmaceutically acceptable salt of a
compound of the invention will have a therapeutic index (the ratio
of the lowest toxic dose to the lowest therapeutically effective
dose) of 1 or greater. The person skilled in the art will recognize
that the lowest therapeutically effective dose will vary from
subject to subject and from indication to indication, and will thus
adjust accordingly.
[0046] The compounds according to the invention are optionally
formulated in a pharmaceutically acceptable vehicle with any of the
well known pharmaceutically acceptable carriers, including diluents
and excipients [see Remington's Pharmaceutical Sciences, 18th Ed.,
Gennaro, Mack Publishing Co., Easton, Pa. 1990 and Remington: The
Science and Practice of Pharmacy, Lippincott, Williams &
Wilkins, 1995]. While the type of pharmaceutically acceptable
carrier/vehicle employed in generating the compositions of the
invention will vary depending upon the mode of administration of
the composition to a mammal, generally pharmaceutically acceptable
carriers are physiologically inert and non-toxic. Formulations of
compositions according to the invention may contain more than one
type of compound of the invention), as well as any other
pharmacologically active ingredient useful for the treatment of the
symptom/condition being treated.
[0047] The compounds of the present invention may be provided in a
pharmaceutically acceptable vehicle using formulation methods known
to those of ordinary skill in the art. The compositions of the
invention can be administered by standard routes, though preferably
administration is by inhalation routes. The compositions of the
invention include those suitable for oral, inhalation, rectal,
ophthalmic (including intravitreal or intracameral), nasal, topical
(including buccal and sublingual), vaginal, or parenteral
(including subcutaneous, intramuscular, intravenous, intradermal,
and intratracheal). In addition, polymers may be added according to
standard methodologies in the art for sustained release of a given
compound.
[0048] Formulations suitable for administration by inhalation
include formulations that can be dispensed by inhalation devices
known to those in the art. Such formulations may include carriers
such as powders and aerosols. The present invention encompasses
liquid and powdered compositions suitable for nebulization and
intrabronchial use, or aerosol compositions administered via an
aerosol unit dispensing metered doses ("MDI"). The active
ingredient may be formulated in an aqueous pharmaceutically
acceptable inhalant vehicle, such as, for example, isotonic saline
or bacteriostatic water and other types of vehicles that are well
known in the art. The solutions are administered by means of a pump
or squeeze-actuated nebulized spray dispenser, or by any other
conventional means for causing or enabling the requisite dosage
amount of the liquid composition to be inhaled into the patient's
lungs. Powder compositions containing the anti-inflammatory
compounds of the present invention include, by way of illustration,
pharmaceutically acceptable powdered preparations of the active
ingredient thoroughly intermixed with lactose or other inert
powders acceptable for intrabronchial administration. The powder
compositions can be administered via a dispenser, including, but
not limited to, an aerosol dispenser or encased in a breakable
capsule which may be inserted by the patient into a device that
punctures the capsule and blows the powder out in a steady stream.
Aerosol formulations for use in the subject method typically
include propellants, surfactants, and co-solvents and may be filled
into conventional aerosol containers that are closed by a suitable
metering valve.
[0049] Formulations of compositions of the present invention
suitable for nasal administration, wherein the carrier is a solid,
include a coarse powder having a particle size, for example, in the
range of 20 to 500 microns which is administered in the manner in
which snuff is administered, i.e., by rapid inhalation through the
nasal passage from a container of the powder held close up to the
nose. Suitable formulations, wherein the carrier is a liquid, for
administration, for example via a nasal spray, aerosol, or as nasal
drops, include aqueous or oily solutions of the compound of the
invention.
[0050] For oral administration, the compositions of the invention
may be presented as discrete units such as capsules, caplets,
gelcaps, cachets, pills, or tablets each containing a predetermined
amount of the active ingredient as a powder or granules; as a
solution or a suspension in an aqueous liquid or a non-aqueous
liquid; or as an oil-in-water liquid emulsion or a water-in-oil
emulsion and as a bolus, etc. Alternately, administration of a
composition of all of the aspects of the present invention may be
effected by liquid solutions, suspensions or elixirs, powders,
lozenges, micronized particles and osmotic delivery systems.
[0051] Formulations of compositions according to the aspects of the
present invention suitable for parenteral administration include
aqueous and non-aqueous sterile injection solutions which may
contain antioxidants, stabilizers, buffers, bacteriostats and
solutes which render the formulation isotonic with the blood of the
intended recipient; and aqueous and non-aqueous sterile suspensions
which may include suspending agents and thickening agents. The
formulations may be presented in unit-dose or multi-dose
containers, for example, sealed ampules and vials, and may be
stored in a freeze-dried (lyophilized) conditions requiring only
the addition of the sterile liquid carrier, for example, water for
injections, immediately prior to use. Extemporaneous injection
solutions and suspensions may be prepared from sterile powders,
granules and tablets of the kind previously described.
[0052] A tablet may be made by compression or molding, optionally
with one or more accessory ingredients. Compressed tablets may be
prepared by compressing, in a suitable machine, the active
ingredient in a free-flowing form such as a powder or granules,
optionally mixed with a binder, lubricant, inert diluent,
preservative, surface active or dispersing agent. Molded tablets
may be made by molding, in a suitable machine, a mixture of the
powdered compound moistened with an inert liquid diluent. The
tablets may be optionally coated or scored and may be formulated to
provide a slow or controlled release of the active ingredient
therein.
[0053] Formulations of compositions of the present invention for
rectal administration may be prepared as a suppository with a
suitable base comprising, such as, for example, cocoa butter.
[0054] Formulations of compositions of the present invention
suitable for topical administration in the mouth include lozenges
comprising the ingredients in a flavored basis, usually sucrose and
acacia or tragacanth; pastilles comprising the active ingredient in
an inert basis such as gelatin and glycerin, or sucrose and acacia;
and mouthwashes comprising the ingredient to be administered in a
suitable liquid carrier. Formulations of compositions of the
present invention suitable for topical administration to the skin
may be presented as ointments, creams, gels, lotions and pastes
comprising the ingredient to be administered in a pharmaceutical
acceptable carrier. A topical delivery system contemplated is a
transdermal patch containing the ingredient to be administered.
[0055] Formulations of compositions according to the aspects of the
present invention suitable for vaginal administration may be
presented as pessaries, suppositories, tampons, creams, gels,
pastes, foams or spray formulations containing in addition to the
compound of the invention such pharmaceutically acceptable carriers
as are known in the art to be appropriate.
[0056] The methods and compositions of the present invention are
intended for use with any mammal that may experience the benefits
of the methods of the invention. Foremost among such mammals are
humans, although the invention is not intended to be so limited,
and is applicable to veterinary uses. Thus, in accordance with the
invention, "mammals" or "mammal in need" include humans as well as
non-human mammals, particularly domesticated animals including,
without limitation, cats, dogs, and horses.
[0057] As used herein, by "treating" is meant reducing, preventing,
and/or reversing the symptoms in the individual to which a compound
of the invention has been administered, as compared to the symptoms
of an individual not being treated according to the invention. A
practitioner will appreciate that the compounds, compositions, and
methods described herein are to be used in concomitance with
continuous clinical evaluations by a skilled practitioner
(physician or veterinarian) to determine subsequent therapy. Hence,
following treatment the practitioners will evaluate any improvement
in reducing cardiovascular risk factors or associated
dyregularities according to standard methodologies. Such evaluation
will aid and inform in evaluating whether to increase, reduce or
continue a particular treatment dose, mode of administration,
etc.
[0058] It will be understood that the subject to which a compound
of the invention is administered need not suffer from a specific
traumatic state. Indeed, the compounds of the invention may be
administered prophylactically, prior to any development of
symptoms. The term "therapeutic," "therapeutically," and
permutations of these terms are used to encompass therapeutic,
palliative as well as prophylactic uses. Hence, as used herein, by
"treating or alleviating the symptoms" is meant reducing,
preventing, and/or reversing the symptoms of the individual to
which a compound of the invention has been administered, as
compared to the symptoms of an individual receiving no such
administration.
[0059] The term "therapeutically effective amount" is used to
denote treatments at dosages effective to achieve the therapeutic
result sought. Furthermore, one of skill will appreciate that the
therapeutically effective amount of the compound of the invention
may be lowered or increased by fine tuning and/or by administering
more than one compound of the invention, or by administering a
compound of the invention with another compound. See, for example,
Meiner, C. L., "Clinical Trials: Design, Conduct, and Analysis,"
Monographs in Epidemiology and Biostatistics, Vol. 8 Oxford
University Press, USA (1986). The invention therefore provides a
method to tailor the administration/treatment to the particular
exigencies specific to a given mammal. As illustrated in the
following examples, therapeutically effective amounts may be easily
determined for example empirically by starting at relatively low
amounts and by step-wise increments with concurrent evaluation of
beneficial effect.
[0060] It will be appreciated by those of skill in the art that the
number of administrations of the compounds according to the
invention will vary from patient to patient based on the particular
medical status of that patient at any given time including other
clinical factors such as age, weight and condition of the mammal
and the route of administration chosen.
[0061] The following examples are intended to further illustrate
certain preferred embodiments of the invention and are not limiting
in nature. Those skilled in the art will recognize, or be able to
ascertain, using no more than routine experimentation, numerous
equivalents to the specific substances and procedures described
herein.
EXAMPLES
Example 1
Effects of Dietary THIAA on Weight Loss and Weight Maintenance
[0062] The purpose of this experiment was to determine the effects
of tetrahydro-isoalpha acid compounds on weight loss and weight
maintenance.
[0063] Animal handling and diets: C57B16/J male mice were 12 weeks
old at the start of the experiment. Twelve mice were maintained
4/cage. Standard diets were purchased from Research Diets, Inc (New
Brunswick, N.J.). The caloric composition of the control diet
("LFD") (D12450B) was 20:70:10 (protein: carbohydrate: fat) and
that of the high fat diet ("HFD) (D12451) was 20:35:45. The
incremental increase in fat was provided by lard. After
establishing that there was taste aversion, the high fat diet was
supplemented with the test agents. Body weight and food consumption
were determined at weekly intervals and adjustments were made if
necessary to insure that the amount of active material THIAA or
Insinase (100 mg kg.sup.-1 d.sup.-1) and rosiglitazone (0.5 mg
kg.sup.-1 d.sup.-1) were delivered.
[0064] Representative animals were sacrificed after twelve weeks
and total body, liver, subcutaneous and gonadal fat weights
determined. Further, some animals were switched to alternative
diets in a cross-over manner (HFD.fwdarw.HFD+THIAA or
HFD+THIAA.fwdarw.HFD) determine the effects of test compounds on
maintaining weight loss or inducing new weight loss.
[0065] Results: At three weeks, all compounds tested resulted in
significantly lowered body weight as compared to HFD diet alone.
Further, by the sixth week, animals on an HFD+THIAA diet displayed
total body weights which were not significantly different than
those for control mice on a LFD alone (FIG. 1).
[0066] From week 16, animals switched from HFD.fwdarw.HFD+THIAA
showed significantly lowered weight as compared to HFD alone
whereas, by week 19 the HFD+THIAA.fwdarw.HFD animals showed
significantly higher body weights as compared to HFD+THIAA alone
(FIG. 2).
[0067] Significant reduction in liver weight (FIG. 3) was observed
in the HFD+THIAA animals as compared to HFD alone. Similar results
were observed for gonadal fat weight in HFD+THIAA or
HFD+THIAA.fwdarw.HFD animals (FIG. 4).
[0068] It was further noted that all compounds tested resulted in
significant loss of subcutaneous body fat as compared to HFD alone
(FIG. 5), which are readily apparent visually either prior to or
post diet switch over (FIGS. 6 and 7 respectively).
Example 2
THIAA increase GLP-1 Secretion in NCI-NIH716 Cell
[0069] The purpose of this experiment was to determine the effect
of THIAA on GLP-1 (glucagon-like peptide-1) synthesis.
[0070] Materials: RPMI 1640 medium, DMEM, l-glutamine, penicillin,
streptomycin, and FBS were purchased from Hyclone Laboratories
(South Logan, Utah). Stocks of THIAA prepared in DMSO at final
concentration of 20 mg/ml. PMA (a known standard for GLP.sub.--1
stimulation) was purchased from Sigma (St. Louis, Mo.). Human
NCI-H716 cells were obtained from the American Type Culture
Collection (Manassas, Va.). Matrigel plates were purchased from BD
biosciences, CA. GLP-1 ELISA kits were purchased from Millipore
(Billerica, Mass.).
[0071] Cell culture: For maintenance, NCIH716 cells were grown in
suspension in RPMI 1640 supplemented with 10% FBS, 2 mm
l-glutamine, 100 IU/ml penicillin, and 100 .mu.g/ml streptomycin.
Cell adhesion and endocrine differentiation were initiated by
growing cells in dishes coated with Matrigel (BD) in high-glucose
DMEM, 10% FBS, 2 mm l-glutamine, 100 IU/ml penicillin, and 100
.mu.g/ml streptomycin (de Bruine A P, Dinjens W N, van der Linden E
P, Pijls M M, Moerkerk P T, Bosman F T 1993 Extracellular matrix
components induce endocrine differentiation in vitro in NCI-H716
cells. Am J Pathol 142:773-782). The NCIH716 cell line, derived
from a poorly differentiated adenocarcinoma of human cecum (Park J
G, Oie H K, Sugarbaker P H, et al. 1987 Characteristics of cell
lines established from human colorectal carcinoma. Cancer Res
47:6710-6718), has been described to display some endocrine
features, in particular the formation of secretory granules and
chromograninA expression (de Bruine A P, Dinjens W N, van der
Linden E P, Pijls M M, Moerkerk P T, Bosman F T 1993 Extracellular
matrix components induce endocrine differentiation in vitro in
NCI-H716 cells. Am J Pathol 142:773-782).
[0072] Cell stimulation: Two-Three days before the experiments, NCI
cells were seeded in 48 well culture plates coated with Matrigel.
On the day of the experiment, cells were washed with serum free
DMEM medium and incubated with serum free DMEM containing with or
without test compounds (THIAA at 20 .mu.g/ml and PMA at 1 .mu.M)
with a final concentration of 0.1% DMSO. Cells were incubated for 2
hrs and the media was immediately analyzed for active GLP-1 (7-36)
using Linco GLP-1 (7-36) active ELISA kit.
[0073] Statistical analysis: GLP-1 levels were normalized with
unstimulated cells (DMSO control) and the data for test compounds
were expressed as fold stimulation. Each experiment represents a
minimum of 3 independent measurements. The final data represent
from 3 independent experiments.
[0074] Results: THIAA increase the GLP-1 secretion about 2.62 fold
in NCI-H716 cells compared to un-stimulated cells (See FIG. 8).
[0075] While the claimed invention has been described in detail and
with reference to specific embodiments thereof, it will be apparent
to one of ordinary skill in the art that various changes and
modifications can be made to the claimed invention without
departing from the spirit and scope thereof. Thus, for example,
those skilled in the art will recognize, or be able to ascertain,
using no more than routine experimentation, numerous equivalents to
the specific substances and procedures described herein. Such
equivalents are considered to be within the scope of this
invention, and are covered by the following claims.
* * * * *